Cranial nerve stimulation to treat seizure disorders

ABSTRACT

A method includes applying, by an implantable medical device (IMD), stimulation to a cranial nerve of a patient responsive to a determination that a level of synchrony between neural activity of one or more regions of an autonomic nervous system of the patient and one or more regions of a central nervous system of the patient falls below a first threshold and discontinuing the application of stimulation by the IMD when the level of synchrony exceeds a second threshold.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/184,789, filed Nov. 8, 2018, which is a continuation of U.S.application Ser. No. 14/316,258, filed Jun. 26, 2014, which claimspriority to U.S. Provisional Application No. 61/840,461, filed Jun. 28,2013, and U.S. Provisional Application No. 61/888,303, filed Oct. 8,2013, all of which are incorporated herein by reference in theirentirety.

FIELD OF THE DISCLOSURE

The present disclosure is generally related to cranial nerve stimulationto treat seizure disorders.

BACKGROUND

Seizures may be treated using cranial nerve stimulation (CNS). CNSincludes application of an electrical stimulation signal to a cranialnerve, e.g., vagus nerve, of a patient. When the cranial nerve is avagus nerve, CNS is referred to as vagus nerve stimulation (VNS).

When used to treat seizure disorders, conventional VNS attempts todecrease synchronization of a patient's interconnected cortical regionsand/or reduces the duration, spatial spread or severity of seizures. VNSin the treatment of seizure disorders typically uses a pattern ofcharge-balanced constant current stimulation at stimulus frequencies of20-30 Hz. Although VNS has proven to be an effective adjunctivetreatment for refractory epilepsy, some patients do not respond to theconventional paradigm of VNS therapy or become unresponsive to thetherapy over time.

SUMMARY

Application of CNS employing microburst signals may produce a change insynchrony between neural activity of one or more regions of a patient'sautonomic nervous system (e.g., the nucleus tractus solitarii (NTS) orother centers responsible for autonomic function regulation) and one ormore regions of the patient's central nervous system (e.g., the thalamusand the cortex). Changing synchrony between one or more regions of apatient's autonomic nervous system and one or more regions of thepatient's central nervous system may have implications in treatment ofepileptic seizures. Systems and methods described herein may provide animproved epileptic seizure treatment.

For example, an implantable medical device (IMD) may determine ameasurement indicative of a synchrony between one or more regions of apatient's autonomic nervous system and one or more regions of a centralnervous system of the patient. Based on the measurement, the IMD maychange the synchrony by applying one or more stimulation signals to acranial nerve of the patient. The IMD may also adjust one or morestimulation parameters and/or change treatment modalities (e.g.,microburst stimulation mode or non-microburst stimulation mode) based ona measurement of synchrony between neural activity of one or moreregions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system. CNS may include VNS,trigeminal nerve stimulation (TNS), or stimulation of another cranialnerve, and the one or more stimulation signals may be applied directlyor indirectly (e.g., transcutaneously).

In a particular embodiment, a method includes determining a firstmeasurement indicative of a synchrony between neural activity of one ormore regions of a patient's autonomic nervous system and one or moreregions of the patient's central nervous system. The method alsoincludes changing the synchrony between the neural activity by applyingone or more stimulation signals to a cranial nerve of the patient basedon the first measurement.

In a particular embodiment, a method includes determining a measurementindicative of a synchrony between neural activity of one or more regionsof a patient's autonomic nervous system and one or more regions of thepatient's central nervous system. The method also includes changing astimulation mode (e.g., from non-micro burst stimulation mode to microburst stimulation mode) based on the measurement.

In a particular embodiment, a device includes a processor configured todetermine a first measurement indicative of a synchrony between neuralactivity of one or more regions of a patient's autonomic nervous systemand one or more regions of the patient's central nervous system. Thedevice further includes a therapy delivery unit electronicallyassociated with the processor and configured to apply one or morestimulation signals to a cranial nerve of the patient based on the firstmeasurement.

In a particular embodiment, a device includes a processor configured todetermine a measurement indicative of a synchrony between neuralactivity of one or more regions of a patient's autonomic nervous systemand one or more regions of a central nervous system of the patient. Thedevice further includes a therapy delivery unit electronicallyassociated with the processor, where the processor is adapted to changea stimulation mode of the therapy delivery unit based on themeasurement.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of a particular embodiment of a system thatuses cranial nerve stimulation to treat seizures;

FIG. 2 is a block diagram of a particular embodiment of a device thatuses cranial nerve stimulation to treat seizures;

FIG. 3 is a diagram illustrating two cortical spike train traces duringapplication of an exemplary non-microburst signal having an amplitude of0.75 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, an ontime of 30 seconds, and an off time of 5 minutes;

FIG. 4 is a diagram illustrating two cortical spike train traces duringapplication of an exemplary non-microburst signal having an amplitude of0.75 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, an ontime of 7 seconds, and an off time of 0.3 minutes;

FIG. 5 is a diagram illustrating two cortical spike train traces duringapplication of an exemplary non-micro burst signal having an amplitudeof 1.25 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, anon time of 30 seconds, and an off time of 5 minutes;

FIG. 6 is a diagram illustrating two NTS spike train traces duringapplication of an exemplary non-microburst signal having an amplitude of0.75 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, an ontime of 30 seconds, and an off time of 5 minutes;

FIG. 7 is a diagram illustrating two NTS spike train traces duringapplication of an exemplary non-microburst signal having an amplitude of0.75 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, an ontime of 7 seconds, and an off time of 0.3 minutes;

FIG. 8 is a diagram illustrating two NTS spike train traces duringapplication of an exemplary non-micro burst signal having an amplitudeof 1.25 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, anon time of 30 seconds, and an off time of 5 minutes;

FIG. 9 is a diagram illustrating two cortical spike train traces duringapplication of an exemplary microburst signal having 5 pulses permicroburst, an amplitude of 0.75 mA, a frequency of 250 Hz, a pulsewidth of 500 microseconds, an interburst period of 0.5 seconds, an ontime of 30 seconds, and an off time of 5 minutes;

FIG. 10 is a diagram illustrating three NTS spike train traces duringapplication of an exemplary microburst signal having 5 pulses permicroburst, an amplitude of 0.75 mA, a frequency of 250 Hz, a pulsewidth of 500 microseconds, an interburst period of 0.5 seconds, an ontime of 30 seconds, and an off time of 5 minutes;

FIG. 11 is a diagram illustrating two cortical spike train traces duringapplication of an exemplary microburst signal having 5 pulses permicroburst, an amplitude of 0.75 mA, a frequency of 250 Hz, a pulsewidth of 500 microseconds, a interburst period of 0.5 seconds, an ontime of 7 seconds, and an off time of 0.3 minutes;

FIG. 12 is a diagram illustrating three NTS spike train traces duringapplication of an exemplary microburst signal having 5 pulses permicroburst, an amplitude of 0.75 mA, a frequency of 250 Hz, a pulsewidth of 500 microseconds, a interburst period of 0.5 seconds, an ontime of 7 seconds, and an off time of 0.3 minutes;

FIG. 13 is a plot of synchrony between neural activity of one or moreregions of a patient's NTS and cortex during a period that includesapplication of one or more particular embodiments of non-micro burstsignals to a cranial nerve of the patient;

FIG. 14 is a plot of latency/delay of one or more regions of a patient'sNTS and cortex during a period that includes application of one or moreparticular embodiments of non-microburst signals to a cranial nerve ofthe patient;

FIG. 15 is a plot of synchrony between neural activity of one or moreregions of a patient's NTS and cortex during a period that includesapplication of one or more particular embodiments of micro burst signalsto a cranial nerve of the patient;

FIG. 16 is a plot of latency/delay of one or more regions of a patient'sNTS and cortex during a period that includes application of one or moreparticular embodiments of microburst signals to a cranial nerve of thepatient;

FIG. 17 is a flow chart of a first particular embodiment of a method ofoperation of an implantable medical device that uses CNS to change asynchrony between neural activity of one or more regions of a patient'sautonomic nervous system and one or more regions of the patient'scentral nervous system;

FIG. 18 is a flow chart of a particular embodiment of a method ofoperation of an implantable medical device that applies one or morestimulation signals to a patient's cranial nerve until a measurement ofsynchrony between one or more regions of the patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemsatisfies a threshold value;

FIG. 19 is a flow chart of a particular embodiment of a method ofoperation of an implantable medical device that applies one or moremicroburst signals and/or one or more non-microburst signal based onwhether one or more measurements of synchrony between one or moreregions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system satisfies a thresholdvalue until one or more synchrony measurements satisfies a thresholdvalue;

FIG. 20 is a flow chart of a particular embodiment of a method ofoperation of an implantable medical device that applies a stimulationsignal to a patient's cranial nerve based on one or more parametersdetermined using a controller of a feedback control loop;

FIG. 21 is a flow chart of a particular embodiment of a method ofoperation of an implantable medical device that changes a stimulationmode of the implantable medical device based on a measurement of asynchrony between one or more regions of a patient's autonomic nervoussystem and one or more regions of the patient's central nervous system;

FIG. 22 is a flow chart of a particular embodiment of a method ofoperation of an implantable medical device that changes a stimulationmode of the implantable medical device based on a measurement ofsynchrony between one or more regions of a patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemusing a controller of a feedback control loop;

FIG. 23 is a power spectrum plot of a neuronal activity of a patient'sautonomic nervous system;

FIG. 24 is a power spectrum plot of a neuronal activity of a patient'scentral nervous system;

FIG. 25 is a plot of synchrony between neural activity of an autonomicnervous system and a central nervous system;

FIG. 26 is a plot of latency/delay between an autonomic nervous systemand a central nervous system;

FIG. 27 shows plots of action potentials in a subject's autonomicnervous system and central nervous system during application ofparticular non-micro burst signals; and

FIG. 28 shows plots of action potentials in a subject's autonomicnervous system and central nervous system during application of aparticular micro burst signal.

DETAILED DESCRIPTION

Disclosed embodiments may enable providing improved therapeuticneurostimulation treatments for a variety of medical conditions based onsynchronicity between neural activity of one or more regions of apatient's autonomic nervous system (e.g., the NTS) and one or moreregions of the central nervous system (e.g., the thalamus and thecortex) of the patient.

As used herein, a “stimulation signal” refers to an electricalstimulation signal delivered to a portion of a patient's body to treat amedical condition by providing a modulating effect to neural tissue. Astimulation signal may be a Cranial Nerve Stimulation (CNS) signal, andthe stimulation signal may be applied directly or indirectly to acranial nerve. A stimulation signal may be a microburst signal, anon-microburst signal, or a combination. The effect of a stimulationsignal on neuronal activity is termed “modulation;” however, forsimplicity, the terms “stimulating” and “modulating,” and variantsthereof, are sometimes used interchangeably herein. In general, however,the delivery of an exogenous signal itself refers to “stimulation” ofthe neural structure, while the effects of that signal, if any, on theelectrical activity of the neural structure are properly referred to as“modulation.” The modulating effect of the stimulation signal upon theneural tissue may be excitatory or inhibitory, and may potentiate acuteand/or long-term changes in neuronal activity. For example, the“modulating” effect of the stimulation signal to the neural tissue maycomprise one more of the following effects: (a) initiation of an actionpotential (afferent and/or efferent action potentials); (b) inhibitionor blocking of the conduction of action potentials, whether endogenousor exogenously induced, including hyperpolarizing and/or collisionblocking; (c) affecting changes m neurotransmitter/neuromodulatorrelease or uptake; and (d) changes in neuro-plasticity or neurogenesisof brain tissue.

As used herein, the autonomic nervous system (ANS or visceral nervoussystem or involuntary nervous system) is the part of the peripheralnervous system that acts as a control system that functions largelybelow the level of consciousness to control visceral functions,including heart rate, digestion, respiratory rate, salivation,perspiration, pupillary dilation, micturition (urination), sexualarousal, breathing and swallowing. Most autonomous functions areinvoluntary but they can often work in conjunction with the somaticnervous system which provides voluntary control.

Within the brain, the ANS is located in the medulla oblongata in thelower brainstem. The medulla's major ANS functions include respiration(the respiratory control center, or “rec”), cardiac regulation (thecardiac control center, or “ccc”), vasomotor activity (the vasomotorcenter or “vmc”), and certain reflex actions (such as coughing,sneezing, vomiting and swallowing). Those are then subdivided into otherareas and are also linked to ANS subsystems and nervous systems externalto the brain. The hypothalamus, just above the brain stem, acts as anintegrator for autonomic functions, receiving ANS regulatory input fromthe limbic system to do so.

The ANS is divided into three main sub-systems: the parasympatheticnervous system (PSNS), the sympathetic nervous system (SNS), and theenteric nervous system (ENS). Depending on the circumstances, thesesub-systems may operate independently of each other or interactco-operatively. Seizure origination and/or propagation may functionallyimpair neural circuits involved in the regulation of an autonomicfunction. Therefore, understanding the relationship between theautonomic nervous system and the central nervous system may help improvethe understanding of the underlying pathology associated with seizuresas well as the efficacy of the therapy applied in order to abortseizures and/or alleviate the overall seizure burden.

As used herein, the term “microburst” refers to at least a portion of astimulation signal including a limited plurality of pulses and a limitedduration. A micro burst may include at least two pulses per burst. Insome embodiments, a microburst may include no more than about 25electrical pulses per burst. In some embodiments, a microburst may havefrom 2 to about 20 pulses per burst. In some embodiments, a microburstmay have from 2 to about 15 pulses per burst. A micro burst may last forno more than 1 second, typically less than 100 milliseconds, e.g., fromabout 10 msec to about 80 msec. A micro burst signal may include aseries of microbursts separated from one another by time intervals knownas “interburst periods.” The interburst periods may allow a refractoryinterval for the nerve to recover from the microburst and again becomereceptive to electrically elicited visual evoked potential (e VEP)stimulation by another microburst. In some embodiments, an interburstperiod may be as long as or longer than adjacent micro bursts (e.g.,micro bursts separated by the interburst period). In some embodiments aninterburst period may have an absolute time period (e.g., duration) ofat least 100 milliseconds. Adjacent pulses in a microburst are separatedby a time interval known as an “interpulse interval.” A “micro burstduration” is a length of a micro burst from the beginning of the firstpulse of a micro burst to the end of the last pulse of the micro burst(and thus the beginning of a new interburst period). A microburstduration may be defined using the microburst's interpulse interval,together with the number of pulses and the pulse width of each pulse.Microburst signals may thus be characterized by an interburst period, amicroburst duration, a number of pulses per microburst, and aninterpulse interval. The pulses in a microburst may be furthercharacterized by a current amplitude and a pulse width. Electricalstimulation according to disclosed embodiments may optionally include anon-time and an off-time in which the microbursts are provided and notprovided, respectively, to a cranial nerve.

In some embodiments, microburst cranial nerve stimulation may be appliedto a patient's cranial nerve by applying a microburst signal to thepatient's cranial nerve. As explained above, the microburst signal maybe a pulsed signal including a series of microbursts separated byinterburst periods. In some embodiments, the interburst periods may havea duration of at least 100 milliseconds each. In other embodiments, theinterburst periods may have a duration of at least the length of one oftwo microbursts separated by the interburst period. In anotherembodiment, the interburst period may be determined for a particularpatient by providing microbursts separated by increasingly smallerinterburst periods. The interburst period may be provided as any timeinterval greater than that at which the e VEP significantly diminishesor disappears. Each micro burst comprises a number of pulses per microburst, an interpulse interval, and has a micro burst duration. In someembodiments, the number of pulses per micro burst may range from 2 toabout 25 pulses, and in another embodiment the number of pulses permicro burst may range from 2 to about 20 pulses, preferably from 2 toabout 15 pulses. The microbursts may be applied to a portion of acranial nerve of the patient. At least one of the interburst period, thenumber of pulses per microburst, the interpulse interval, or themicroburst duration may be selected to enhance cranial nerve evokedpotentials.

Pulses within a microburst may also have a pulse width and a currentamplitude. In some embodiments, the method may also comprise anoff-time, during which microbursts are not applied to the patient and anon-time during which microbursts are applied to the patient. It may beconvenient to refer to a burst frequency, defined as 1 divided by thesum of the micro burst duration and the interburst period, and it willbe recognized by persons of skill in the art that the interburst periodmay alternatively be described in terms of a frequency of the pulsesrather than as an absolute time separating one pulse from another. Pulseshapes in electrical signals may include a variety of shapes includingsquare waves, biphasic pulses (including active and passivecharge-balanced biphasic pulses), triphasic waveforms, etc. In oneembodiment, the pulses comprise a square, biphasic waveform in which thesecond phase is a charge-balancing phase of the opposite polarity to thefirst phase.

In some embodiments, conventional cranial nerve stimulation (e.g.,“non-microburst” stimulation) may be applied. In this case, anon-microburst signal may be defined by a current amplitude, a pulsewidth, a frequency, an on-time, and an off-time. The non-microburstsignal typically has more than about 50 pulses per burst and a burstduration of at least about 7 seconds.

In some embodiments, a method may include applying a primary mode ofcranial nerve stimulation during a first period and a secondary mode ofcranial nerve stimulation during a second period. In some embodiments,the primary mode may be conventional cranial nerve stimulation (e.g.,stimulation by application of one or more non-micro burst signals), andthe secondary mode may be microburst cranial nerve stimulation (e.g.,stimulation by application of one or more microburst signals). In otherembodiments, the primary mode may be microburst cranial nervestimulation and the secondary mode may be conventional cranial nervestimulation. When the primary mode is conventional cranial nervestimulation, the first period may correspond to the on-time ofconventional cranial nerve stimulation and the second time period maycorrespond to the off-time of conventional cranial nerve stimulation. Inanother embodiment, the first period and the second period can partiallyoverlap. In another embodiment, one of the first period or the secondperiod can be entirely overlapped by the other of the first period orthe second period.

Referring to FIG. 1, a block diagram of a system 100 that uses CNS totreat seizures of a patient 102 (e.g., an epilepsy patient) is shownaccording to an exemplary embodiment. CNS may include vagus nervestimulation (VNS), trigeminal nerve stimulation (TNS), stimulation ofother cranial nerves, or a combination thereof. The system 100 mayinclude an implantable medical device (IMD) 104, a sensor datacollection system 106, and an external programming device 108. The IMD104 may include a processor 110, a memory 112, a data gathering unit114, a therapy delivery unit (TDU) 116, a power storage unit 118, atransceiver 120, and a system bus 124. The processor 110 may be a singleprocessor of the IMD 104 or multiple processors of the IMD 104. Thememory 112 may include instructions 122 that are executable by theprocessor 110 to operate the IMD 104. The system 100 may include acontroller 123 of a feedback control loop, which may be a part of (oroperate in conjunction with) the processor 110 and the memory 112. Insome embodiments, the controller 123 may include software (instructions)stored in the memory 112 and executable by the processor 110.

The data gathering unit 114 may gather data related to an operationalstate of the IMD 104 (e.g., a charge state of the power storage unit118), data related to therapy provided to the patient 102, bodyparameter data corresponding to one or more body parameters of thepatient 102, or a combination thereof. Data gathered by the datagathering unit 114 may be used to control therapy provided to thepatient 102, may be transmitted to an external device, or both.

The TDU 116 may be configured to provide therapy to the patient 102. Forexample, the TDU 116 may provide electrical stimulation (via one or moreelectrodes (not shown)) to tissue of the patient 102. The TDU 116 mayprovide electrical stimulation to the cranial nerve (e.g., the vagusnerve, the trigeminal nerve, etc.) of the patient 102. Therapy providedby the TDU 116 may be controlled by the processor 110. The power storageunit 118 may provide electrical power to components of the IMD 104and/or to the IMD 104. For example, the power storage unit 118 may be abattery. The transceiver 120 may enable the IMD 104 to communicate withother devices, such as the sensor data collection system 106 and theexternal programming device 108. The processor 110, the memory 112, thedata gathering unit 114, the TDU 116, the power storage unit 118, andthe transceiver 120 may be connected via the system bus 124.

The sensor data collection system 106 may include a processor 126, amemory 128, a sensor data gathering unit 130, a power storage unit 132,a transceiver 134, and a system bus 138. The processor 126 may be asingle processor of the sensor data collection system 106 or may includemultiple processors of the sensor data collection system 106. The memory128 may include instructions 136 that are executable by the processor126 to operate the sensor data collection system 106.

The sensor data gathering unit 130 may be configured to collect bodyparameter data from one or more sensors placed on, in, and/or near thepatient 102. Activity of one or more regions of the patient's centralnervous system and/or one or more regions of the patient's autonomicnervous system may be measured using body parameter data collected fromsensors placed in the patient's central nervous system and/or autonomicnervous system. Alternatively, or in addition, activity in the patient'scentral nervous system and/or autonomic nervous system may be measuredusing body parameter data collected form sensors that are placed on thesurface of the body of the patient. For example, surface electrodesplaced on the head of the patient may be used to record a far-fieldvisual evoked potential (VEP), which originates from regions of theforebrain, using EEG equipment typically used clinically for recordingsomatosensory or auditory evoked potentials.

As examples, an electroencephalography (EEG) sensor(s) 140, anelectrooculography (EOG) sensor(s) 142, an electrocardiography (ECG)sensor(s) 144, an electromyography (EMG) sensor(s) 146, and anaccelerometer(s) 148 may be placed on the patient 102 to sense a bodyparameter data of the patient 102, or a part of the patient 102. A firstsensor may be placed in, on or near the patient 102 to sense a bodyparameter data of at least a portion of the patient's central nervoussystem. A second sensor may be placed in, on or near the patient 102 tosense body parameter data of at least a portion of the patient'sautonomic nervous system. The body parameter data may include EEG data,EOG data, ECG data, respiration data, EMG data, accelerometer data, or acombination thereof. In some embodiments, the body parameter data mayinclude EEG data indicative of neural activity of (or associated with)the patient's central nervous system and local field potentials orspiking activity data indicative of neural activity of (or associatedwith) the patient's autonomic nervous system. The sensor data gatheringunit 130 may receive the body parameter data via respective wired orwireless connections to the EEG sensor(s) 140, the EOG sensor(s) 142,the ECG sensor(s) 144, the EMG sensor(s) 146, and the accelerometer(s)148.

In some embodiments, body parameter data may include spike train dataindicative of a sequence of neuronal action potentials of one or moreneurons in one or more regions of the patient's autonomic nervous systemand spike train data indicative of a sequence of neuronal actionpotentials of one or more neurons in one or more regions of thepatient's central nervous system.

In some embodiments, body parameter data may include a neuronal firingrate of one or more neurons of one or more regions of the patient'scentral nervous system and a neuronal firing rate one or more neurons ofone or more regions of the patient's autonomic nervous system. In someembodiments, the body parameter data may include a continuous timeseries of brain activity associated with the patient's central nervoussystem and a continuous time series of brain activity associated withthe patient's autonomic nervous system.

The power storage unit 132 may be configured to provide electrical powerto components of the sensor data collection system 106 and/or to thesensor data collection system 106. For example, the power storage unit132 may include a battery. The transceiver 134 may be configured toenable the sensor data collection system 106 to communicate with otherdevices, such as the IMD 104 and the external programming device 108.The processor 126, the memory 128, the sensor data gathering unit 130,the power storage unit 132, and the transceiver 134 may be connected viathe system bus 138.

The external programming device 108 may include a transceiver 150 and anantenna 152. The transceiver 150 may be configured to communicate (e.g.,transmit data, receive data, or a combination thereof) via the antenna152 with the IMD 104. For example, the external programming device 108may send program data, such as therapy parameter data to the IMD 104using wireless signals. The program data may be stored at a memory 158of the external programming device 108, may be received from a computingdevice 160, or both.

The external computing device 160 may include a processor 162, a memory164, a communication interface 166, a display 168, other components (notshown), or a combination thereof. The external computing device 160 mayreceive data from the external programming device 108, the sensor datacollection system 106, the IMD 104, or a combination thereof, via thecommunication interface 166 and may store the data in the memory 164.The external computing device 160 may provide an interface (e.g., viathe display 168) to the patient 102 and/or to a health care provider tosee the stored data. The stored data may be used to facilitatedetermining information regarding efficacy of a therapy.

During operation, the sensor data collection system 106 may collect thebody parameter data from the EEG sensor(s) 140, the EOG sensor(s) 142,the ECG sensor(s) 144, the EMG sensor(s) 146, the accelerometer 148, ora combination thereof. In a particular embodiment, the sensor datacollection system 106 may collect body parameter data from one or moreareas of the patient's body other than the patient's brain. The sensordata collection system 106 may measure body parameter data in the formof neural activity at the patient's autonomic nervous system and neuralactivity at the patient's central nervous system. The sensor datacollection system 106 may communicate the body parameter data to the IMD104 occasionally (e.g., periodically) or continuously. The sensor datacollection system 106 may communicate the body parameter data to the IMD104 in real time (e.g., as soon as the sensor data collection system 106receives the body parameter data) or in near-real time (e.g., afterperforming pre-processing such as filtering, grouping (such as bywindow), formatting, or a combination thereof).

A measurement indicative of synchrony between neural activity of one ormore regions of the autonomic nervous system of the patient 102 and oneor more regions of the central nervous system of the patient maysometimes be referred to herein as a “synchrony measurement.” Based onthe body parameter data, the IMD 104 (e.g., the processor 110)determines a measurement (e.g., a “first synchrony measurement”)indicative of synchrony between neural activity of one or more regionsof the autonomic nervous system of the patient 102 and one or moreregions of the central nervous system of the patient 102 for a window(e.g., a “first window”) of body parameter data. The first window maycorrespond to a particular time span during which body parameter data isgathered. Alternatively, the first window may be defined based on aparameter other than time, such as one or more stimulation parameters.For example, a first window may begin at a start of an on-time period ofa stimulation signal and may end at a start of an off-time period of thestimulation signal. The first synchrony measurement may be in the formof a rate of change of a value indicative of synchrony between neuralactivity of one or more regions of the patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemduring the first window. The first synchrony measurement may also, or inthe alternative, be in the form of a measure of latency of communicationbetween one or more regions of the patient's autonomic nervous systemand one or more regions of the patient's central nervous system duringthe first window. The first synchrony measurement may also, or in thealternative, be determined using body parameter data collected by thesensor data collection system 106 from one or more areas of thepatient's body other than the patient's brain (e.g., heart ratevariability data, heart rate morphology data, or a combination thereof).The first synchrony measurement may also, or in the alternative, bedetermined using measurements collected by the sensor data collectionsystem 106 of neural activity at the patient's autonomic nervous systemand the patient's central nervous system.

The IMD 104 may determine the first synchrony measurement using a linearmeasure (e.g., cross-correlation and coherence) or nonlinear measure(e.g., mutual information, transfer entropy, granger causality,nonlinear interdependence, and phase synchronization) of the bodyparameter data. For example, the IMD 104 may determine the firstsynchrony measurement by determining a cross-correlation of dataindicative of neuronal firing rates of one or more neurons of one ormore regions of the patient's central nervous system during the firstwindow and data indicative of neuronal firing rates of one or moreneurons of one or more regions of the patient's autonomic nervous systemduring the first window.

The IMD 104 may determine the first synchrony measurement usingtime-scale dependent spike train distances (e.g., Victor-Purpuradistance, van Rossum distance, Schreiber et al. similarity measure,Population extensions) or using time-scale independent spike traindistances (e.g., Event synchronization, !SI-distance, SPIKE-distance).For example, the IMD 104 may determine the first synchrony measurementby determining a Victor-Purpura distance of spike train data for one ormore regions of a patient's autonomic nervous system during the firstwindow and spike train data for one or more regions of a patient'scentral nervous system during the first window.

Based on the first synchrony measurement, the IMD 104 may apply one ormore stimulation signals (e.g., a “first stimulation signal”) to acranial nerve (e.g., vagus nerve) of the patient 102. When applied tothe patient, the one or more stimulation signals may change thesynchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system. For example, the one or morestimulation signals may include one or more microburst signals, andapplying the one or more micro burst signals may increase synchronybetween neural activity of one or more regions of the patient'sautonomic nervous system and one or more regions of the patient'scentral nervous system.

The IMD 104 (e.g., the TDU 116) may apply the one or more stimulationsignals to the patient based on a determination by the processor 110that the first synchrony measurement indicates a seizure state (e.g.,ongoing seizure, onset of a seizure, and/or imminent onset of a seizure)or non-seizure state (e.g., no ongoing seizure, seizure termination,and/or imminent termination of a seizure). In some embodiments, thethreshold value may be a value indicative of a threshold level ofsynchrony (e.g., a “threshold synchrony value”) between neural activityof one or more regions of the patient's autonomic nervous system and oneor more regions of the patient's central nervous system.

In some embodiments, the processor 110 may determine that the firstsynchrony measurement indicates a seizure state by determining that thefirst synchrony measurement satisfies a threshold synchrony valueindicative of onset of a seizure. For example, onset of a seizure may beindicated by a low (relative to a non-seizure state) synchrony betweenneural activity of one or more regions of the patient's autonomicnervous system and one or more regions of the patient's central nervoussystem. Thus, the threshold synchrony level may be selected tocorrespond to a low (relative to a non-seizure state) level of synchronybetween one or more regions of the patient's autonomic nervous systemand one or more regions of the patient's central nervous system. Thefirst synchrony measurement may be determined to satisfy the thresholdsynchrony value when the first synchrony measurement (e.g., using theprocessor 110) indicates that synchrony between neural activity of oneor more regions of the patient's autonomic nervous system and one ormore regions of the patient's central nervous system is below thethreshold synchrony value. For example, the IMD 104 may apply one ormore microburst signals to a patient's vagus nerve in response to theprocessor 110 determining that the first synchrony measurement indicatesthat synchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system satisfies (e.g., is below) a thresholdsynchrony value indicative of onset of a seizure.

As a further example, onset of a seizure may be indicated by synchronybetween neural activity of one or more regions of the patient'sautonomic nervous system and one or more regions of the patient'scentral nervous system that decreases at a rate greater than or equal toa rate corresponding to a threshold synchrony value (in the form of arate of change as described above). Thus, a threshold synchrony valueindicative of a seizure state (e.g., seizure onset) may be selected tocorrespond to a rate of change (e.g., rate of decrease) of synchronybetween neural activity of one or more regions of the patient'sautonomic nervous system and one or more regions of the patient'scentral nervous system. The first synchrony measurement (e.g., in theform of a rate of change of synchrony) may be determined to satisfy thethreshold synchrony level when the first synchrony measurement (e.g.,using the processor 110) indicates that the synchrony between the neuralactivity of one or more regions of the patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemis decreasing at a rate at least as fast the threshold synchrony value.For example, the IMD 104 may apply one or more microburst signals to apatient's vagus nerve in response to the processor 110 determining thatthe first synchrony measurement indicates that synchrony between neuralactivity of one or more regions of the patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemsatisfies (e.g., is decreasing at a rate equal to or greater than) thethreshold synchrony value.

In some embodiments, the processor 110 may determine that the firstsynchrony measurement indicates a non-seizure state by determining thatthe first synchrony measurement satisfies a threshold synchrony valueindicative of termination of a seizure. For example, termination of aseizure may be indicated by higher (relative to when the patient isexperiencing a seizure) synchrony between neural activity of one or moreregions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system. Thus, the thresholdsynchrony level may be selected to correspond to a higher (relative to aseizure state) level of synchrony between one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system. The first synchrony measurement may bedetermined to satisfy the threshold synchrony value when an evaluationof the first synchrony measurement (e.g., using the processor 110)indicates that the synchrony between neural activity of one or moreregions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system is above the thresholdsynchrony value. For example, the IMD 104 may apply one or moremicroburst stimulation signals to a patient's vagus nerve until theprocessor 110 determines that a synchrony measurement of the patientindicates that synchrony between neural activity of one or more regionsof the patient's autonomic nervous system and one or more regions of thepatient's central nervous system satisfies (e.g., exceeds) a thresholdsynchrony value indicative of a non-seizure state (e.g., that thepatient's seizure has ended).

As a further example, termination of a seizure may be indicated bysynchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system that increases at least at a ratecorresponding to a threshold synchrony value. Thus, a thresholdsynchrony value indicative of a non-seizure state (e.g., seizuretermination) may be selected to correspond to a rate of change (e.g.,rate of increase) of synchrony between neural activity of one or moreregions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system. The first synchronymeasurement (e.g., in the form of a rate of change of synchrony) may bedetermined to satisfy the threshold synchrony value when an evaluationof the first synchrony measurement (e.g., using the processor 110)indicates that the synchrony between the neural activity of one or moreregions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system is increasing at a rateat least as fast the threshold synchrony value. For example, the IMD 104may apply one or more microburst signals to a patient's vagus nerve inresponse to the processor 110 determining that the first synchronymeasurement indicates that synchrony between neural activity of one ormore regions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system satisfies (e.g., isincreasing at a rate greater than) the threshold synchrony value.

Alternatively, or in addition, based on the first synchrony measurement,the IMD 104 may change its stimulation mode from a first stimulationmode (e.g., a micro burst stimulation mode) to a second stimulation mode(e.g., a non-microburst stimulation mode). In a microburst stimulationmode, the IMD 104 (e.g., TDU 116) is configured to apply one or moremicroburst signals to a cranial nerve of the patient, and in a non-microburst stimulation mode, the IMD 104 (e.g., TDU 116) is configured toapply one or more non-microburst signals to a cranial nerve of thepatient.

The IMD 104 may change its stimulation mode from the first stimulationmode to the second stimulation mode based on a determination by theprocessor 110 that the first synchrony measurement satisfies a thresholdvalue. In some embodiments, the threshold value may be a thresholdsynchrony value.

In some embodiments, the threshold synchrony value may be a valueindicative of a seizure state (e.g., onset or imminent onset of aseizure). For example, the IMD 104 may be operating, or set to operate,in a non-microburst stimulation mode prior to determining that the firstsynchrony measurement satisfies a threshold synchrony value indicativeof onset of a seizure. Based on determining that the first synchronymeasurement satisfies the threshold synchrony value, the IMD 104 maychange its stimulation mode from the non-micro burst stimulation mode tothe micro burst stimulation mode (e.g., the IMD 104 may instruct the TDU116 to apply one or more microburst signals to a patient's vagus nervein response to the processor 110 determining that the first synchronymeasurement satisfies the threshold synchrony value). Alternatively, theIMD 104 may be operating, or set to operate, in a microburst stimulationmode prior to determining that the first synchrony measurement satisfiesthe threshold synchrony value indicative of onset of a seizure. Based ondetermining that the first synchrony measurement satisfies the thresholdsynchrony value, the IMD 104 may change its stimulation mode from themicroburst stimulation mode to the non-microburst stimulation mode(e.g., the IMD 104 may instruct the TDU 116 to apply one or morenon-micro burst signals to a patient's vagus nerve in response to theprocessor 110 determining that the first synchrony measurement satisfiesthe threshold synchrony value).

In some embodiments, the threshold synchrony value may be a valueindicative of a non-seizure state (e.g., termination of a seizure). Forexample, the IMD 104 may be operating, or set to operate, in anon-microburst stimulation mode prior to determining that the firstsynchrony measurement satisfies a threshold synchrony value indicativeof termination of a seizure. Based on determining that the firstsynchrony measurement satisfies the threshold synchrony value, the IMD104 may change its stimulation mode from the non-microburst stimulationmode to the micro burst stimulation mode (e.g., the IMD 104 may instructthe TDU 116 to apply one or more microburst signals to a patient's vagusnerve in response to the processor 110 determining that the firstsynchrony measurement satisfies the threshold synchrony value).Alternatively, the IMD 104 may be operating, or set to operate, in amicro burst stimulation mode prior to determining that the firstsynchrony measurement satisfies the threshold synchrony value indicativeof termination of a seizure. Based on determining that the firstsynchrony measurement satisfies the threshold synchrony value, the IMD104 may change its stimulation mode from the micro burst stimulationmode to the non-micro burst stimulation mode (e.g., the IMD 104 mayinstruct the TDU 116 to apply one or more non-microburst signals to apatient's vagus nerve in response to the processor 110 determining thatthe first synchrony measurement satisfies the threshold synchronyvalue).

The IMD 104 may additionally determine a synchrony measurement (e.g., a“second synchrony measurement”) after application of a first stimulationsignal of the one or more stimulation signals is initiated. The secondsynchrony measurement may be based on body parameter data collected bythe sensor data collection system 106 after application of the firststimulation signal is initiated (e.g., for a “second window” of bodyparameter data that begins after application of the first signal isinitiated). The second window may correspond to a particular time spanduring which body parameter data is gathered. Alternatively, the secondwindow may be defined based on a parameter other than time, such as oneor more stimulation parameters. For example, the second window of bodyparameter data may begin at a start of an on-time period of thestimulation signal and may end at a start of an off-time period of thefirst stimulation signal. The second synchrony measurement may beprovided to the controller 123 of the feedback control loop thatdetermines a stimulation parameter of a second stimulation signal,determines whether to change a stimulation mode, or both. The controller123 may be a proportional/integral (PI) controller, aproportional/integral/derivative (PID) controller, or some othercontroller that functions as described in greater detail with referenceto FIG. 2.

FIG. 2 is a block diagram of a particular embodiment of an IMD 104 ofFIG. 1 that includes a controller 123 to determine one or moreparameters of the second stimulation signal, whether to change asimulation mode of the IMD, or both. The controller 123 may be a part of(or operate in conjunction with) the processor 110 and the memory 112 ofFIG. 1. In some embodiments, the controller 123 may include software(instructions) stored in the memory 112 and executable by the processor110 of FIG. 1. With reference to FIG. 2, the data gathering unit 114 mayreceive body parameter data or other measurements 202 from the sensordata collection system 106 of FIG. 1, and may output a “second synchronymeasurement” 208 to the controller 123. In some embodiments, the datagathering unit 114 processes the body parameter data 114 in conjunctionwith the processor 110 to determine the second synchrony measurementfrom the received body parameter data 114. The controller 123 compares,at 214, the second synchrony measurement 208 to a setpoint 212 todetermine an error value 216. The setpoint 212 may be a value indicativeof a baseline synchrony level of the patient, e.g., a value indicativeof a synchrony level of the patient prior to seizure onset. The setpoint212 may be a predicted value. For example, the setpoint 212 maycorrespond to a synchrony level that is predicted by a model to presentin response to application of the first stimulation signal to thepatient. The error value 216 may be processed by the controller 123 todetermine a control variable value 218. The controller 123 may use thecontrol variable value 218 to determine a value of at least onestimulation parameter of a second stimulation signal. Alternatively, orin addition, the controller 123 may use the control variable value todetermine a stimulation mode of the IMD 104 (e.g., microburststimulation mode or non-microburst stimulation mode of the IMD 104). Thecontroller 123 may provide a control signal 204 to the TDU 116. The TDU116 may change its stimulation mode in response to receiving the controlsignal 204 indicative of the stimulation mode. The TDU 116 may apply asecond stimulation signal to the patient. The second stimulation signalmay have a value of a stimulation parameter based on stimulationparameter information from the control signal 204. For example,controller 123 may determine that, based on the input error value 216and the parameters of the first stimulation signal, an amplitude of thesecond stimulation signal should be changed (e.g., increased) to asecond value. The TDU 116 may apply the second stimulation signal 206having an amplitude corresponding to the second value responsive toreceiving the control signal 204.

FIGS. 3-8 illustrate exemplary body parameter data (e.g., spike traindata) as spike train traces of one or more neurons during application ofone or more non-microburst signals. The body parameter data in FIGS. 3-8may be collected by the sensor data collection system 106 of FIG. 1 andprovided to the IMD 104 of FIGS. 1 and 2.

Spike train traces 302 and 304 of FIGS. 3, 402 and 404 of FIG. 4, and502 and 504 of FIG. 5 illustrate spike train data as spike train tracesof one or more neurons of a patient's parietal cortex during applicationof non-microburst signals 306, 406, and 506 to a vagus nerve,respectively. To gather the spike traces 302 and 304, the non-microburstsignal 306 had the following stimulation parameters: 0.75 mA, 30 Hz, 500microsecond pulsewidth, 30 second on-time, and 5 min off-time. To gatherthe spike traces 402 and 404, the non-microburst signal 406 had thefollowing parameters: 0.75 mA, 30 Hz, 500 microsecond pulsewidth, 7second on-time and 0.3 minute off-time. To gather the spike traces 502and 504, the non-microburst signal 506 had the following parameters:1.25 mA, 30 Hz, 500 microsecond pulsewidth, 30 second on-time and 5minute off-time. As indicated by the spike traces of FIGS. 3-5,application of non-microburst signals does not elicit substantialcortical activation.

Spike train traces 602 and 604 of FIGS. 6, 702 and 704 of FIG. 7, and802 and 804 of FIG. 8 illustrate spike train data of one or more neuronsof one or more regions of a patient's NTS during application ofnon-microburst signals 606, 706, and 806, respectively. To gather thespike traces 602 and 604, the non-microburst signal 606 had thefollowing parameters: 0.75 mA, 30 Hz, 500 microseconds pulsewidth, 30second on-time, and 5 minute off-time. To gather the spike traces 702and 704, the non-microburst signal 706 had the following parameters:0.75 mA, 30 Hz, 500 microseconds pulsewidth, 7 second on-time, and 0.3minute off-time. To gather the spike traces 802 and 804, thenon-microburst signal 806 had the following parameters: 1.25 mA, 30 Hz,500 microseconds pulsewidth, 30 second on-time, and 5 min off-time. Incontrast to response of the parietal cortex to application ofnon-microburst signals, application of non-microburst signals increasedNTS neuronal activity significantly during the stimulation phase (asindicated by the spike traces of FIGS. 6-8).

FIGS. 9-12 illustrate exemplary body parameter data (e.g., spike traindata) as spike train traces of one or more neurons during application ofone or more microburst signals. The body parameter data in FIGS. 9-12may be collected by the sensor data collection system 106 of FIG. 1 andprovided to the IMD 104 of FIGS. 1 and 2. Spike train traces of 902 and904 of FIG. 9 and spike train traces 1102 and 1104 of FIG. 11 illustratespike train data as spike train traces of one or more neurons of apatient's parietal cortex during application of microburst signals 906and 1106. To gather the spike train traces 902 and 904, micro burstsignal 906 had the following stimulation parameters: 0.75 mA, 250 Hz,500 microseconds pulsewidth, 5 pulses per microburst, 0.5 secondinterburst period, 30 seconds on-time, and 5 minutes off-time. To gatherthe spike train traces 1102 and 1104, microburst signal 1106 had thefollowing parameters: 0.75 mA, 250 Hz, 500 microseconds pulsewidth, 5pulses per microburst, 0.5 second interburst period, 7 seconds on-time,and 0.3 minutes off-time. Spike train traces 1002, 1004, and 1006 ofFIG. 10 and 1202, 1204, and 1206 of FIG. 12 illustrate spike train dataas spike train traces of one or more neurons of a patient's NTS duringapplication of microburst signals 1008 and 1208, respectively. To gatherthe spike train traces 1002, 1004, and 1006, micro burst signal 1008 hadthe following parameters: 0.75 mA, 250 Hz, 500 microseconds pulsewidth,5 pulses per microburst, 0.5 second interburst period, 30 secondson-time, and 5 minutes off-time. To gather the spike train traces 1202,1204, and 1206, microburst signal 1208 had the following parameters:0.75 mA, 250 Hz, 500 microseconds pulsewidth, 5 pulses per microburst,0.5 second interburst period, 7 seconds on-time, and 0.3 minutesoff-time. As indicated by the spike train traces of FIGS. 9-12,application of microburst stimulation signals increases corticalactivity without substantial NTS potentiation.

FIGS. 13 and 15 are plots of one or more synchrony measurements. Togenerate FIG. 13, non-microburst signals were applied at times indicatedby arrows 1302, 1306, 1312, and 1316. In FIG. 13, as indicated bytroughs 1304, 1308, 1314, and 1318, synchrony appears to decrease inresponse to application of the non-micro burst signals. To generate FIG.15, micro burst signals were applied at times indicated by arrows 1502,1506, 1512, and 1516. In FIG. 15, as indicated by peaks 1504, 1508,1514, and 1518, synchrony appears to increase in response to applicationof the micro burst signals.

FIGS. 14 and 16 are plots of neuronal latency/delay between an NTS andcortex. To generate FIG. 14, non-microburst signals were applied attimes indicated by arrows 1402, 1406, 1412, and 1416. In FIG. 14,latency/delay does not appear to consistently decrease in response tothe non-microburst signals. To generate FIG. 16, microburst signals wereapplied at times indicated by arrows 1602, 1606, 1612, and 1616. In FIG.16, as indicated by peaks 1604, 1608, 1614, and 1618, latency/delayappears to decrease in response to application of the microburstsignals.

As illustrated in FIGS. 3-12, NTS and cortical regions responddifferently to application of micro burst stimulation and non-microburst stimulation. Neural activity in cortical regions can be increasedby application of microburst signals. Activity in NTS regions can beincreased using non-microburst signals; however, non-microburst signalsdo not appear to activate cortical regions. In contrast to applicationof non-microburst signals, synchrony between one or more regions of anNTS and one or more regions of a cortex may be substantially increasedby application of micro burst signals.

FIG. 17 is a flow chart of a particular embodiment of a method oftreating seizure disorders using an implantable medical device. Forexample, the method 1700 may be performed using the IMD 104 of FIG. 1 inconjunction with the sensor data collection system 106 of FIG. 1.

The method 1700 includes determining a synchrony measurement (e.g.,“first synchrony measurement”) of the patient, at 1702, for a firstwindow of body parameter data. The window of body parameter data maycorrespond to a particular time span during which body parameter data isgathered. Alternatively, the window of body parameter data may bedefined based on a parameter other than time, such as one or morestimulation parameters. For example, a window of body parameter data maybegin at a start of an on-time period of a stimulation signal and mayend at a start of an off-time period of a stimulation signal. The firstsynchrony measurement may be determined by the processor 110 of the IMD104 of FIG. 1 using body parameter data from the sensor data collectionsystem 106 as described above. The first synchrony measurement may be inthe form of a rate of change of a value indicative of synchrony betweenneural activity of one or more regions of the patient's autonomicnervous system and one or more regions of the patient's central nervoussystem. The first synchrony measurement may also, or in the alternative,be in the form of a measure of latency of communication between one ormore regions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system. The first synchronymeasurement may also, or in the alternative, be determined usingmeasurements collected by the sensor data collection system 106 ofneural activity at one or more regions of the patient's autonomicnervous system and one or more regions of the patient's central nervoussystem. The first synchrony measurement may also be determined usingbody parameter data collected by the sensor data collection system 106from one or more areas of the patient's body other than the patient'sbrain (e.g., heart rate variability data, heart rate morphology data, ora combination thereof).

The method 1700 may further include changing the synchrony level ofneural activity of one or more regions of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system by applying a first stimulation signalbased on the first synchrony measurement, at 1704. In some embodiments,application of the first stimulation signal may be controlled and/orperformed using the TDU 116 of FIG. 1. In some embodiments, the firststimulation signal may be a micro burst signal (e.g., 906, 1008, 1106,1208 of FIGS. 9-12). In some embodiments, when applied to the patient,the first stimulation signal may increase a synchrony between neuralactivity of one or more regions of one or more regions of the patient'sautonomic nervous system and one or more regions of the patient'scentral nervous system. In some embodiments, the first stimulationsignal may be a non-microburst signal.

The first stimulation signal may be applied based on a determinationthat the first synchrony measurement indicates a seizure state (e.g.,onset and/or imminent onset of a seizure) as described above. In someembodiments, the processor 110 determines whether the synchronymeasurement indicates a seizure state (e.g., by determining whether thefirst synchrony measurement satisfies a threshold synchrony value asdescribed above).

Synchrony between neural activity of one or more regions of a patient'sautonomic nervous system and one or more regions of a patient's centralnervous system may decrease at a relatively high rate and/or be at asubstantially low level (relative to a non-seizure state) during theseizure state; the rate of decrease and/or relatively low level may beindicative of the seizure state (e.g., an ongoing seizure and/or onsetor imminent onset of a seizure). Thus, the method of FIG. 17 may includechanging (e.g., increasing) a synchrony between one or more regions ofthe patient's autonomic nervous system and one or more regions of thepatient's central nervous system by applying one or more stimulationsignals (e.g., microburst signals).

In some embodiments, changing the synchrony between neural activity ofone or more regions of the patient's autonomic nervous system and one ormore regions of the patient's central nervous system based on the firstsynchrony measurement includes increasing the synchrony between neuralactivity of one or more regions of the patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemby applying one or more micro burst signals to a cranial nerve of thepatient. For example, one or more micro burst signals (e.g., 906, 1008,1106, 1208 in FIGS. 9-12) may be applied. As illustrated in FIG. 15,application of one or more microburst signals to a patient's cranialnerve may increase synchrony between neural activity of one or moreregions of a patient's NTS and one or more regions of the patient'scortex. In FIG. 15, microburst signals were applied at times indicatedby arrows 1502, 1506, 1512, and 1516. As indicated by peaks 1504, 1508,1514, and 1518, synchrony between one or more regions of the patient'sautonomic nervous system (e.g. NTS) and the patient's central nervoussystem (e.g. cortex) was increased by application of one or moremicroburst signals.

FIG. 18 is a flow chart of a particular embodiment of a method 1800 oftreating seizure disorders by changing a synchrony between neuralactivity of a patient using an implantable medical device to apply oneor more stimulation signals until a synchrony between neural activity ofone or more regions of the patient's autonomic nervous system and one ormore regions of the patient's central nervous system satisfies athreshold value. For example, the method 1800 may be performed using theIMD 104 in conjunction with the sensor data collection system 106 ofFIG. 1.

The method 1800 may include determining a synchrony measurement (e.g., a“first synchrony measurement”) of the patient, at 1802, for a firstwindow of body parameter data (e.g., a “first window”). The first windowmay correspond to a particular time span during which body parameterdata is gathered. Alternatively, the first window may be defined basedon a parameter other than time, such as one or more stimulationparameters. For example, a first window may begin at a start of anon-time period of a stimulation signal and may end at a start of anoff-time period of a stimulation signal. The first synchrony measurementmay be determined by the processor 110 of the IMD 104 of FIG. 1 usingbody parameter data from the sensor data collection system 106 asdescribed above.

The method 1800 may further include determining whether the firstsynchrony measurement satisfies a threshold value, at 1804. In someembodiments, the processor 110 determines whether the first synchronymeasurement satisfies a threshold value. The threshold value may be avalue indicative of a threshold level of synchrony (e.g., a “thresholdsynchrony value”) between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system. In some embodiments, the thresholdsynchrony value may be a value indicative of a threshold rate of changeof synchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system.

In some embodiments, the threshold synchrony value may be indicative ofa non-seizure state (e.g., seizure termination) as described above. Forexample, in embodiments in which the threshold synchrony value isindicative of a non-seizure state (e.g., seizure termination), themethod may include applying one or more microburst signals until thefirst synchrony measurement satisfies the threshold synchrony value,thereby indicating that the patient is no longer experiencing a seizure.In response to determining that the first synchrony measurementsatisfies the threshold synchrony value, micro burst stimulation may bediscontinued (e.g. in favor of application of non-microburststimulation). Alternatively, or in addition, the method may includeapplying one or more non-microburst signals until the first synchronymeasurement satisfies the threshold synchrony value, thereby indicatingthat the patient is no longer experiencing a seizure. In response todetermining that the first synchrony measurement satisfies thethreshold, non-micro burst stimulation may be discontinued (e.g. infavor of application of microburst stimulation). In some embodiments,the threshold synchrony value may be (e.g., selected to be) a valueindicative of a threshold rate of change of synchrony associated withseizure termination, and the first synchrony measurement may be in theform of a rate of change of synchrony, as described above.

In some embodiments, the threshold synchrony value may be indicative ofa seizure state (e.g., onset of a seizure) as described above. Forexample, in embodiments in which the threshold synchrony value isindicative of a seizure state (e.g., onset of a seizure), the method mayinclude applying one or more non-microburst signals until the synchronymeasurement satisfies the threshold synchrony value, thereby indicatingonset of a seizure. In response to determining that the synchronymeasurement satisfies the threshold synchrony value, non-microburststimulation may be discontinued (e.g. in favor of application of microburst stimulation). Alternatively, or in addition, the method mayinclude applying one or more microburst signals until the synchronymeasurement satisfies the threshold synchrony value, thereby indicatingseizure onset. In response to determining that the synchrony measurementsatisfies the threshold synchrony value, micro burst stimulation may bediscontinued (e.g. in favor of application of non-microburststimulation). In some embodiments, the threshold synchrony value may be(e.g., selected to be) a value indicative of a threshold rate of changeof synchrony associated with seizure onset, and the first synchronymeasurement may be in the form of a rate of change of synchrony, asdescribed above. A threshold rate of change of synchrony value may beselected such that the rate of change indicates onset of a seizure.

A threshold rate of change of synchrony value may alternatively beselected such that the rate of change indicates that the stimulation isbecoming ineffective (e.g., when the rate of change of a synchronymeasurement satisfies the threshold rate of change value, the currentstimulation parameters are sufficiently ineffective to produce desiredresponse and should be adjusted). For example, micro burst stimulationmay be applied to a patient at onset of a seizure event as describedabove. During the seizure event, at 1802, a synchrony measurement (inthe form of a rate of change of synchrony) of the patient may bedetermined. The synchrony measurement may be compared to the thresholdrate of change of synchrony. When it is determined that the synchronymeasurement satisfies the threshold rate of change value, microburststimulation may be discontinued in favor of non-microburst stimulationduring the seizure event. Alternatively, when it is determined that thesynchrony measurement satisfies the threshold rate of change value, amicroburst stimulation parameter may be adjusted in response todetermining that the synchrony measurement satisfies the threshold rateof change value.

Any one or more synchrony measurements, threshold values, andstimulation signals of a particular iteration of 1800 may be differentthan any one or more synchrony measurements, threshold values, andstimulation signals of a subsequent iteration of 1800. For example,during a first iteration of 1800, a first synchrony measurement may bedetermined, at 1802, based on a first window of body parameter data, anda first stimulation signal (e.g., a first micro burst signal) may beapplied at 1806. During a subsequent iteration of 1800 (e.g., when thefirst synchrony measurement does not satisfy the threshold synchronyvalue, at 1804), a second synchrony measurement may be determined basedon a second window of body parameter data and a second stimulationsignal (e.g., a “second micro burst signal”) may be applied, at 1806.The second window may or may not include different body parameter datathan the first window. The second stimulation signal (e.g., the secondmicro burst signal) may or may not include one or more differentstimulation parameters than the first stimulation signal (e.g., thefirst microburst signal). For example, the second synchrony measurementmay indicate that the first stimulation signal did not produce asatisfactory synchrony response (e.g., did not sufficiently increase thesynchrony). To increase the efficacy of the stimulation therapy, one ormore stimulation signal parameters (e.g., amplitude, microburstduration, etc.) may be adjusted such that the second stimulation signalhas different parameters (e.g., greater amplitude) than the firststimulation signal.

FIG. 19 is a flow chart of a particular method of treating seizures thatincludes evaluating one or more synchrony measurements of the patient todetermine occurrence of a seizure, and evaluating the same, ordifferent, one or more of the patient's synchrony measurements todetermine whether to apply a microburst or non-microburst signal when aseizure is determined to be occurring. For example, the method of FIG.19 may be performed using the IMD 104 in conjunction with the sensordata collection system 106 of FIG. 1.

The method 1900 may include determining a synchrony measurement (e.g., a“first synchrony measurement”), at 1904, for a first window of bodyparameter data. The first window of body parameter data may correspondto a particular time span during which body parameter data of thepatient is gathered. Alternatively, the first window of body parameterdata may be defined based on a parameter other than time, such as one ormore stimulation parameters. For example, a window of body parameterdata may begin at a start of an on-time period of a stimulation signaland may end at a start of an off-time period of a stimulation signal.The first synchrony measurement may be determined by the processor 110of the IMD 104 in FIG. 1 using body parameter data from the sensor datacollection system 106 as described above.

The method 1900 may further include determining whether the firstsynchrony measurement satisfies a first threshold value, at 1906. Insome embodiments, the first threshold value may be a threshold synchronyvalue (e.g., a “first threshold synchrony value”) associated with aseizure state (e.g., an ongoing seizure and/or onset of a seizure) or anon-seizure state (e.g., seizure termination), as described above. Whenthe first threshold synchrony value is associated with a seizure state,the first synchrony measurement may satisfy the first thresholdsynchrony value at onset of a seizure as described above. When the firstthreshold synchrony value is associated with a non-seizure state, thefirst synchrony measurement may satisfy may the threshold synchronyvalue at termination of a seizure as described above.

The method 1900 may further include determining whether the firstsynchrony measurement satisfies a second threshold value, at 1910, whenthe first synchrony measurement satisfies the first threshold value, at1906. In some embodiments, the processor 110 of FIG. 1 determineswhether the first synchrony measurement satisfies the second thresholdvalue, at 1910. The second threshold value may be a threshold synchronyvalue (e.g., a “second threshold synchrony value”). The first thresholdvalue may be the same as or different than the second threshold value.The first and second threshold values used during a first iteration ofthe method of FIG. 19 may be the same as or different than thecorresponding first and second threshold values used in one or moresubsequent iterations. For example, in some embodiments, a firstthreshold value of a first iteration of the method 1900 may be selectedto be indicative of seizure onset as described above, while a firstthreshold value of a subsequent iteration of 1900 may be selected to beindicative of seizure termination as described above, where the firstthreshold value indicative of a seizure onset is different than thefirst threshold value indicative of seizure termination.

As a further example, a second threshold value of a first iteration ofthe method 1900 and a subsequent iteration may be in the form of athreshold rate of change of synchrony as described above. The secondthreshold value of the first iteration may be different than the secondthreshold value of the subsequent iteration. For example, the secondthreshold value of the subsequent iteration may be adjusted to begreater than or less than the second threshold value of the firstiteration because the rate of change of synchrony may be expected todecrease as the patient builds a tolerance to stimulation therapy.

The method 1900 may further include applying a microburst signal (e.g.,906, 1008, 1106, 1208 of FIGS. 9-12), at 1912, when the first synchronymeasurement does not satisfy the second threshold value. In someembodiments, application of the microburst signal may be controlledand/or performed using TDU 116 of FIG. 1. In some embodiments, whenapplied to the patient, the microburst signal may increase a synchronybetween neural activity of one or more regions of the patient'sautonomic nervous system and one or more regions of the patient'scentral nervous system.

The method 1900 may further include applying a non-microburst signal(e.g., 306, 406, 506, 606, 706, 806 of FIGS. 3-8), at 1914, when thefirst synchrony measurement satisfies the threshold value. In someembodiments, application of the non-micro burst signal may increase asynchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system.

The method 1900 returns to 1904 to perform a subsequent iteration of themethod of FIG. 19 as described above.

FIG. 20 is a flow chart of a particular method of treating a seizuredisorder by determining a stimulation parameter of a stimulation signal.For example, the method of FIG. 20 may be performed using the controller123 of FIG. 1. The controller 123 may be a PI controller, a PIDcontroller, or some other controller configured to perform operations asdescribed with reference to FIG. 20.

The method 2000 may include determining a synchrony measurement (e.g., a“second synchrony measurement”), at 2002, for a window (e.g., a “secondwindow”) of body parameter data. The second window of body parameterdata may be collected by the sensor data collection system 106 afterapplication of a first stimulation signal is initiated (e.g., the secondwindow begins after application of the first stimulation signal isinitiated). The second window may correspond to a particular time spanduring which body parameter data is gathered. Alternatively, the secondwindow may be defined based on a parameter other than time, such as oneor more stimulation parameters. For example, the second window of bodyparameter data may begin at a start of an on-time period of thestimulation signal and may end at a start of an off-time period of thefirst stimulation signal.

The method 2000 further includes processing, at 2004 (e.g., using theprocessor 110 of FIG. 1), the second synchrony measurement to determinean error between the second synchrony measurement and a setpoint. Insome embodiments, the setpoint is a predicted value of a response of thepatient to application of the first stimulation signal and is predictedbased on a model. In some embodiments, the setpoint may be a thresholdsynchrony value indicative of a baseline synchrony level of the patient(e.g., a synchrony level of the patient when the patient is notexperiencing a seizure). At least one stimulation parameter may bedetermined (e.g., using the processor 110 of FIG. 1) based on a controlvariable value determined using the error, at 2006. For example, in someembodiments, an amplitude value of a stimulation signal may bedetermined based on the error. In other embodiments, the at least onestimulation parameter may include a stimulation parameter other thanamplitude.

The method 2000 further includes applying, at 2008, a second stimulationsignal to one or more cranial nerves of the patient based on the atleast one stimulation parameter (e.g., using the TDU 116 of FIG. 1). Thesecond stimulation signal may be a microburst signal (e.g., 906, 1008,1106, 1208 in FIGS. 9-12). For example, in some embodiments, where atleast one stimulation parameter determined, at 2006, is an amplitude ofa stimulation signal, the second stimulation signal may be set to havean amplitude equal to, or based on, the amplitude value determined, at2006.

FIG. 21 is a flow chart of a particular embodiment of a method oftreating seizure disorders using an implantable medical device (e.g.,the IMD 104 of FIG. 1). The method 2100 includes changing a stimulationmode of the implantable medical device based on a measurement ofsynchrony between one or more regions of a patient's autonomic nervoussystem and one or more regions of the patient's central nervous system.For example, the method 2100 may be performed using the IMD 104 inconjunction with the sensor data collection system 106 of FIG. 1. Themethod includes determining a synchrony measurement of the patient, at2102, for a window (e.g., a “first window”) of body parameter data asdescribed above. The window of body parameter data may correspond to aparticular time span during which body parameter data is gathered.Alternatively, the window of body parameter data may be defined based ona parameter other than time, such as one or more stimulation parameters.For example, a window of body parameter data may begin at a start of anon-time period of a stimulation signal and may end at a start of anoff-time period of a stimulation signal. The synchrony measurement maybe determined by the processor 110 of the IMD 104 in FIG. 1 using bodyparameter data from the sensor data collection system 106 as describedabove.

The method 2100 further includes changing a stimulation mode of the IMD104 from a first stimulation mode (e.g., microburst or non-microburststimulation mode) to a second stimulation mode (e.g., micro burst ornon-micro burst stimulation mode) based on the first synchronymeasurement, at 2104. In the microburst stimulation mode, the IMD 104(e.g., using the TDU 116) is configured to apply one or more microburstsignals to a cranial nerve of the patient. In the non-microburststimulation mode, the IMD 104 (e.g., using the TDU 116) is configured toapply one or more non-micro burst signals to a cranial nerve of thepatient.

The IMD 104 may change its stimulation mode from a first stimulationmode (e.g., micro burst or non-micro burst) to a second stimulation mode(e.g., micro burst or non-micro burst) based on a determination by theprocessor 110 that the synchrony measurement satisfies a thresholdsynchrony value.

In some embodiments, the threshold synchrony value may be indicative ofa seizure state as described above. The IMD 104 of FIG. 1 may change itsstimulation mode in response to determining that the synchronymeasurement satisfies the threshold synchrony value indicative of theseizure state.

For example, the IMD 104 may be operating, or set to operate, in anon-microburst stimulation mode prior to determining that the firstsynchrony measurement satisfies a threshold synchrony value indicativeof the seizure state (e.g., seizure onset). The IMD 104 may change itsstimulation mode from non-microburst stimulation mode to microburststimulation mode in response to the processor 110 determining that thefirst synchrony measurement indicates that synchrony between neuralactivity of one or more regions of the patient's autonomic nervoussystem and one or more regions of the patient's central nervous systemsatisfies (e.g., is below, is decreasing at a rate greater than, orboth) a threshold synchrony value indicative of onset of a seizure.

As another example, the IMD 104 may be operating, or set to operate, ina microburst stimulation mode prior to determining that the firstsynchrony measurement satisfies a threshold synchrony value indicativeof onset of the seizure state (e.g., seizure onset). The IMD 104 maychange its stimulation mode from microburst stimulation mode tonon-microburst stimulation mode in response to determining that thesynchrony measurement satisfies the threshold synchrony value. Forexample, the IMD 104 may change its stimulation mode from micro burststimulation mode to non-micro burst stimulation mode in response to theprocessor 110 determining that the first synchrony measurement indicatesthat synchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system satisfies (e.g., is below, isdecreasing at a rate greater than, or both) the threshold synchronyvalue.

In some embodiments, the threshold synchrony value may be indicative ofa non-seizure state as described above. The IMD 104 may change itsstimulation mode in response to determining that the synchronymeasurement satisfies the threshold synchrony value indicative of thenon-seizure state.

For example, the IMD 104 may be operating, or set to operate, m amicroburst stimulation mode prior to determining that the firstsynchrony measurement satisfies a threshold synchrony value indicativeof a non-seizure state (e.g., seizure termination). The IMD 104 maychange its stimulation mode from microburst stimulation mode tonon-microburst stimulation mode in response to the processor 110determining that the first synchrony measurement indicates thatsynchrony between neural activity of one or more regions of thepatient's autonomic nervous system and one or more regions of thepatient's central nervous system satisfies (e.g., is above, isincreasing at a rate greater than, or both) a threshold synchrony valueindicative of termination of a seizure.

As another example, the IMD 104 may be operating, or set to operate, m anon-microburst stimulation mode prior to determining that the firstsynchrony measurement satisfies a threshold synchrony value indicativeof a non-seizure state (e.g., seizure termination). The IMD 104 maychange its stimulation mode from non-microburst stimulation mode tomicroburst stimulation mode in response to the processor 110 determiningthat the first synchrony measurement indicates that synchrony betweenneural activity of one or more regions of the patient's autonomicnervous system and one or more regions of the patient's central nervoussystem satisfies (e.g., is above, is increasing at a rate greater than,or both) a threshold synchrony value indicative of termination of aseizure.

FIG. 22 is a flow chart of a particular method of treating a seizuredisorder. The method of FIG. 22 includes changing a stimulation mode ofa medical device using a controller. The controller may be a PIcontroller, a PID, or some other controller configured to performoperations described with reference to FIG. 22.

The method 2200 may include determining a synchrony measurement (e.g., a“second synchrony measurement”), at 2202, for a window (e.g., a “secondwindow”) of body parameter data. The second window of body parameterdata collected by the sensor data collection system 106 afterapplication of a first stimulation signal is initiated (e.g., the secondwindow begins after application of the first signal is initiated). Thesecond window may correspond to a particular time span during which bodyparameter data is gathered. Alternatively, the second window may bedefined based on a parameter other than time, such as one or morestimulation parameters. For example, the second window of body parameterdata may begin at a start of an on-time period of the stimulation signaland may end at a start of an off-time period of the first stimulationsignal.

The method 2200 further includes processing the second synchronymeasurement, at 2204, (e.g., using the processor 110 of FIG. 1) todetermine an error between the second synchrony measurement and asetpoint. In some embodiments, the setpoint is a predicted value of aresponse of the patient to application of the first stimulation signaland is predicted based on a model. In some embodiments, the setpoint maybe a value indicative of a baseline synchrony level of the patient.

The method 2200 further includes determining a control variable valueindicative of whether to change a stimulation mode of the IMD 104, at2206. For example, the control variable value may be a value of aparticular stimulation parameter corresponding to a particularstimulation mode different than the stimulation mode in which the IMD104 is set or operating. For example, the IMD 104 may be operating, orset to operate, in a non-microburst stimulation mode when the secondsynchrony measurement is determined, at 2202. A control variable valuein the form of a stimulation parameter value (e.g., micro burstduration) corresponding to operation in microburst stimulation mode maybe determined, at 2206. The control variable value may be a valueindicative of a seizure state (e.g., ongoing seizure, seizure onset,and/or imminent seizure onset) or a non-seizure state (e.g., terminationof a seizure and/or imminent seizure termination). For example, the IMD104 may be operating or set in a non-microburst stimulation mode whenthe second synchrony measurement is determined, at 2202. A controlvariable value indicating a seizure state or a non-seizure state may bedetermined, at 2206.

The method 2200 further includes changing the stimulation mode of theIMD 104 based on the control variable value, at 2206. For example, theIMD 104 may be operating, or set to operate, in a non-micro burststimulation mode. A control value indicative of a seizure state (e.g.,onset of a seizure) may be determined, at 2206. Based on determining thecontrol variable value indicative of onset of the seizure, the IMD 104may change its stimulation mode to a micro burst stimulation mode (e.g.,may cause the TDU 116 to apply microburst stimulation). As anotherexample, the IMD 104 may be operating, or set to operate, in a microburst stimulation mode. A control variable value indicative of anon-seizure state (e.g., seizure termination) may be determined, at2206. Based on determining the control variable value indicative oftermination of the seizure, the IMD 104 may change its stimulation modeto a non-microburst stimulation mode (e.g., the IMD 104 may instruct theTDU 116 to apply non-microburst stimulation).

FIGS. 23 and 24 represent body parameter data such as measurementsindicative of neural activity of one or more regions of a subject's NTSand cortex, respectively. FIG. 25 illustrates synchrony measurementdetermined based on the body parameter data illustrated in FIGS. 23 and24. FIG. 26 illustrates a synchrony measurement in the form of a plot oflatency between the subject's NTS and one or more regions of thesubject's cortex. To generate FIGS. 23-26, a seizure was induced at 600seconds. As illustrated in FIGS. 25 and 26, a synchrony between neuralactivity of the measured regions of the NTS and cortex decreases duringa seizure. Thus, a treatment that increases synchrony between one ormore regions of the patient's autonomic nervous system and one or moreregions of the patient's central nervous system may be useful intreating seizure disorders.

FIGS. 27 and 28 illustrate results of acute electrophysiologicalexperiments in rats under alpha-chloralose anesthesia. The experimentsincluded assaying neuron activity in both the initial brain destinationof vagal afferents (ipsilateral medial nucleus of the solitarytract—mNTS) as well as the parietal cortex. Extracellular actionpotentials were recorded using high impedance electrodes simultaneouslyin each location. Principal component analysis techniques identified anaverage of 3 neurons per site per experiment (n=IO rats). FIG. 27illustrates graphs of action potentials in the parietal cortex and NTSwhen non-micro burst signals (current intensities of 0.25-0.75 mA, pulsewidth of 500 psec) at 30 Hz were applied. FIG. 28 illustrates graphs ofaction potentials in the parietal cortex and NTS when microburst signalsmicroburst signals (5 pulses, pulse width of 500 psec at 250 Hz every0.5 s) were applied.

With reference to trace 2704 of FIG. 27, non-microburst signals (currentintensities of 0.25-0.75 mA, pulse width of 500 psec) at 30 Hz increasedNTS neuronal activity significantly during the stimulation phase.Specifically, Activation of cervical vagus axons at 30 Hz evokedsynchronous action potentials in the NTS at latencies averaging 16±1 ms.Following VNS using non-microburst signals, action potentials persistedin amplitude beyond the stimulus period. This persistent dischargelikely represents a developing neuronal synchronization beginning at lowamplitude (e.g., a few neurons) and gradually increasing in amplitude(e.g., more neurons). This suggests recruitment of additional NTSneurons that were inactive during baseline unstimulated conditions. Incontrast, with reference to trace 2702 of FIG. 27, parietal cortexinduced changes in activity were not detected. Thus, non-microburstsignals at 30 Hz effectively synchronized and potentiated the amplitudeof the neuronal activity in the NTS without causing significant changesin cortical activity.

With reference to trace 2804 of FIG. 28, application of the micro burstsignals (5 pulses, pulse width of 500 μsec at 250 Hz every 0.5 s) evokedsingle action potentials in the NTS with every shock (0.25-0.75 mA) withlatencies ranging from 8-50 ms. The latencies suggested activation ofmyelinated A,B-fibers and unmyelinated C-fibers, respectively. Withreference to trace 2802 of FIG. 28, VNS using microburst signals alsoactivated short latency action potentials in the parietal cortex withlatencies ranging from 20-50 ms. Spontaneous cortical activity decreasedsignificantly during the non-stimulating phase of microburst VNS from6.6±3.1 Hz to 1.6±0.3 Hz. Thus, microburst signals effectivelyfacilitated short latency neuronal responses in both the NTS and theparietal cortex. Consequently, the cortical activity significantlydecreased during the unstimulated periods. Since the parietal cortexreceives direct projections from limbic structures, the data showed thatmicroburst VNS effectively recruited long lasting activation of thecentral neuroaxis. Non-microburst signals effectively increasedsynchrony between the subject's NTS and cortex.

Although the description above contains many specificities, thesespecificities are utilized to illustrate some of the exemplaryembodiments of this disclosure and should not be construed as limitingthe scope of the disclosure. The scope of this disclosure should bedetermined by the claims and their legal equivalents. A method or devicedoes not have to address each and every problem to be encompassed by thepresent disclosure. All structural, chemical and functional equivalentsto the elements of the disclosure that are known to those of ordinaryskill in the art are expressly incorporated herein by reference and areintended to be encompassed by the present claims. A reference to anelement in the singular is not intended to mean one and only one, unlessexplicitly so stated, but rather it should be construed to mean at leastone. No claim element herein is to be construed under the provisions of35 U.S.C. § 112, sixth paragraph, unless the element is expresslyrecited using the phrase “means for.” Furthermore, no element, componentor method step in the present disclosure is intended to be dedicated tothe public, regardless of whether the element, component or method stepis explicitly recited in the claims.

The disclosure is described above with reference to drawings. Thesedrawings illustrate certain details of specific embodiments thatimplement the systems and methods of the present disclosure. However,describing the disclosure with drawings should not be construed asimposing on the disclosure any limitations that may be present in thedrawings. The present disclosure contemplates methods, systems andprogram products on any machine-readable media for accomplishing itsoperations. The embodiments of the present disclosure may be implementedusing an existing computer processor, or by a special purpose computerprocessor incorporated for this or another purpose or by a hardwiredsystem.

As noted above, embodiments within the scope of the present disclosureinclude program products comprising computer readable storage device, ormachine-readable media for carrying, or having machine-executableinstructions or data structures stored thereon. Such machine readablemedia can be any available media which can be accessed by a generalpurpose or special purpose computer or other machine with a processor.By way of example, such machine readable media can comprise RAM, ROM,EPROM, EEPROM, CD ROM or other optical disk storage, magnetic diskstorage or other magnetic storage devices, or any other medium which canbe used to carry or store desired program code in the form ofmachine-executable instructions or data structures and which can beaccessed by a general purpose or special purpose computer or othermachine with a processor. The disclosure may be utilized in anon-transitory media. When information is transferred or provided over anetwork or another communications connection (either hardwired,wireless, or a combination of hardwired or wireless) to a machine, themachine properly views the connection as a machine-readable medium.Thus, any such a connection is properly termed a machine-readablemedium. Combinations of the above are also included within the scope ofmachine-readable media. Machine-executable instructions comprise, forexample, instructions and data which cause a general purpose computer,special purpose computer, or special purpose processing machines toperform a certain function or group of functions.

Embodiments of the disclosure are described in the general context ofmethod steps which may be implemented in one embodiment by a programproduct including machine executable instructions, such as program code,for example, in the form of program modules executed by machines innetworked environments. Generally, program modules include routines,programs, objects, components, data structures, etc., that performparticular tasks or implement particular abstract data types.Machine-executable instructions, associated data structures, and modulesrepresent examples of program code for executing steps of the methodsdisclosed herein. The particular sequence of such executableinstructions or associated data structures represent examples ofcorresponding acts for implementing the functions described in suchsteps.

Embodiments of the present disclosure may be practiced in a networkedenvironment using logical connections to one or more remote computershaving processors. Logical connections may include a local area network(LAN) and a wide area network (WAN) that are presented here by way ofexample and not limitation. Such networking environments are commonplacein office-wide or enterprise-wide computer networks, intranets and theInternet and may use a wide variety of different communicationprotocols. Those skilled in the art will appreciate that such networkcomputing environments will typically encompass many types of computersystem configurations, including personal computers, hand-held devices,multiprocessor systems, microprocessor-based or programmable consumerelectronics, network PCs, servers, minicomputers, mainframe computers,and the like. Embodiments of the disclosure may also be practiced indistributed computing environments where tasks are performed by localand remote processing devices that are linked (either by hardwiredlinks, wireless links, or by a combination of hardwired or wirelesslinks) through a communications network. In a distributed computingenvironment, program modules may be located in both local and remotememory storage devices.

An exemplary system for implementing the overall system or portions ofthe disclosure might include a general purpose computing device in theform of a computer, including a processing unit, a system memory, and asystem bus that couples various system components including the systemmemory to the processing unit. The system memory may include read onlymemory (ROM) and random access memory (RAM). The computer may alsoinclude a magnetic hard disk drive for reading from and writing to amagnetic hard disk, a magnetic disk drive for reading from or writing toa removable magnetic disk, and an optical disk drive for reading from orwriting to a removable optical disk such as a CD ROM or other opticalmedia. The drives and their associated machine-readable media providenonvolatile storage of machine executable instructions, data structures,program modules, and other data for the computer.

It should be noted that although the flowcharts provided herein show aspecific order of method steps, it is understood that the order of thesesteps may differ from what is depicted. Also two or more steps may beperformed concurrently or with partial concurrence. Such variation willdepend on the software and hardware systems chosen and on designerchoice. It is understood that all such variations are within the scopeof the disclosure. Likewise, software and web implementations of thepresent disclosure could be accomplished with standard programmingtechniques with rule based logic and other logic to accomplish thevarious database searching steps, correlation steps, comparison stepsand decision steps. It should also be noted that the word “component” asused herein and in the claims is intended to encompass implementationsusing one or more lines of software code, and/or hardwareimplementations and/or equipment for receiving manual inputs.

The foregoing descriptions of embodiments of the disclosure have beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the disclosure to the precise formdisclosed, and modifications and variations are possible in light of theabove teachings or may be acquired from practice of the disclosure. Theembodiments were chosen and described in order to explain the principalsof the disclosure and its practical application to enable one skilled inthe art to utilize the disclosure in various embodiments and withvarious modifications as are suited to the particular use contemplated.

The illustrations of the embodiments described herein are intended toprovide a general understanding of the structure of the variousembodiments. The illustrations are not intended to serve as a completedescription of all of the elements and features of apparatus and systemsthat utilize the structures or methods described herein. Many otherembodiments may be apparent to those of skill in the art upon reviewingthe disclosure. Other embodiments may be utilized and derived from thedisclosure, such that structural and logical substitutions and changesmay be made without departing from the scope of the disclosure. Forexample, method steps may be performed in a different order than isshown in the figures or one or more method steps may be omitted.Accordingly, the disclosure and the figures are to be regarded asillustrative rather than restrictive.

Moreover, although specific embodiments have been illustrated anddescribed herein, it should be appreciated that any subsequentarrangement designed to achieve the same or similar results may besubstituted for the specific embodiments shown. This disclosure isintended to cover any and all subsequent adaptations or variations ofvarious embodiments. Combinations of the above embodiments, and otherembodiments not specifically described herein, will be apparent to thoseof skill in the art upon reviewing the description.

The Abstract of the Disclosure is submitted with the understanding thatit will not be used to interpret or limit the scope or meaning of theclaims. In addition, in the foregoing Detailed Description, variousfeatures may be grouped together or described in a single embodiment forthe purpose of streamlining the disclosure. This disclosure is not to beinterpreted as reflecting an intention that the claimed embodimentsrequire more features than are expressly recited in each claim. Rather,as the following claims reflect, the claimed subject matter may bedirected to less than all of the features of any of the disclosedembodiments.

What is claimed is:
 1. A method comprising: applying, by an implantablemedical device (IMD), stimulation to a cranial nerve of a patientresponsive to a determination that a level of synchrony between neuralactivity of one or more regions of an autonomic nervous system of thepatient and one or more regions of a central nervous system of thepatient falls below a first threshold; and discontinuing the applicationof stimulation by the IMD when the level of synchrony exceeds a secondthreshold.
 2. The method of claim 1, wherein the first thresholdcorresponds to a level of synchrony indicative of the onset of aseizure.
 3. The method of claim 1, wherein the second thresholdcorresponds to a level of synchrony indicative of a non-seizure state.4. The method of claim 1, wherein the first threshold and the secondthreshold correspond to a rate of change of the level of synchrony. 5.The method of claim 1, wherein the stimulation is applied in a firststimulation mode, the method further comprising applying, by the IMD,stimulation to the cranial nerve of the patient in a second stimulationmode in response to discontinuing the application of stimulation in thefirst stimulation mode.
 6. The method of claim 5, wherein the firststimulation mode comprises microburst stimulation and the secondstimulation mode comprises non-microburst stimulation.
 7. The method ofclaim 5, wherein the first stimulation mode comprises non-microburststimulation and the second stimulation mode comprises microburststimulation.
 8. The method of claim 1, further comprising determining,based on body parameter data collected by one or more sensors positionedon the patient, a first measurement indicative of the level ofsynchrony.
 9. An implantable medical device (IMD) comprising: aprocessor; and a memory device having instructions stored thereon that,when executed by the processor, causes the processor to performoperations comprising: applying, by one or more electrodes, stimulationto a cranial nerve of a patient responsive to a determination that alevel of synchrony between neural activity of one or more regions of anautonomic nervous system of the patient and one or more regions of acentral nervous system of the patient falls below a first threshold; anddiscontinuing the application of stimulation when the level of synchronyexceeds a second threshold.
 10. The IMD of claim 9, wherein the firstthreshold corresponds to a level of synchrony indicative of the onset ofa seizure.
 11. The IMD of claim 9, wherein the second thresholdcorresponds to a level of synchrony indicative of a non-seizure state.12. The IMD of claim 9, wherein the first threshold and the secondthreshold correspond to a rate of change of the level of synchrony. 13.The IMD of claim 9, wherein the stimulation is applied in a firststimulation mode, the operations further comprising applying, by the oneor more electrodes, stimulation to the cranial nerve of the patient in asecond stimulation mode in response to discontinuing the application ofstimulation in the first stimulation mode.
 14. The IMD of claim 13,wherein the first stimulation mode comprises microburst stimulation andthe second stimulation mode comprises non-microburst stimulation. 15.The IMD of claim 13, wherein the first stimulation mode comprisesnon-microburst stimulation and the second stimulation mode comprisesmicroburst stimulation.
 16. The IMD of claim 9, the operations furthercomprising determining, based on body parameter data collected by one ormore sensors positioned on the patient, a first measurement indicativeof the level of synchrony.
 17. A computer-readable storage mediumstoring instructions thereon that, when executed by a processor of animplantable medical device (IMD), cause the IMD to: apply stimulation toa cranial nerve of a patient responsive to a determination that a levelof synchrony between neural activity of one or more regions of anautonomic nervous system of the patient and one or more regions of acentral nervous system of the patient falls below a first threshold; anddiscontinue the application of stimulation when the level of synchronyexceeds a second threshold.
 18. The computer-readable storage medium ofclaim 17, wherein the first threshold corresponds to a level ofsynchrony indicative of the onset of a seizure and wherein the secondthreshold corresponds to a level of synchrony indicative of anon-seizure state.
 19. The computer-readable storage medium of claim 17,wherein the first threshold and the second threshold correspond to arate of change of the level of synchrony.
 20. The computer-readablestorage medium of claim 17, wherein the stimulation is applied in afirst stimulation mode, the instructions further causing the IMD toapply stimulation to the cranial nerve of the patient in a secondstimulation mode in response to discontinuing the application ofstimulation in the first stimulation mode.